Donald “D.A.” Henderson, an American epidemiologist who led the international war on smallpox that resulted in its eradication in 1980, the only such vanquishment in history of a human disease and an achievement that was credited with saving tens of millions of lives, died Aug. 19 at a hospice facility in Towson, Md. He was 87.

The cause was complications from a broken hip, said his daughter, Leigh Henderson.

A self-described “disease detective,” Dr. Henderson spent the defining years of his career as an official of the Centers for Disease Control and Prevention and the World Health Organization. Later, he served as dean of Johns Hopkins University’s school of public health and as a science and bioterrorism adviser in three presidential administrations.

But it was in the fight on smallpox — perhaps the most lethal disease in history and one that killed an estimated 300 million people in the 20th century alone — that he became known around the world. Lent from the CDC to the WHO for a decade in the 1960s and 1970s, he commanded a small cadre of public-health officials and an army of field workers in an endeavor that amounted to a medical moonshot.

“I think it can be fairly said that the smallpox eradication was the single greatest achievement in the history of medicine,” Richard Preston, the best-selling author of volumes including “The Hot Zone,” about the Ebola virus, and “The Demon in the Freezer,” about smallpox, said in an interview. He described Dr. Henderson as a “Sherman tank of a human being — he simply rolled over bureaucrats who got in his way.”

D.A. Henderson in 1974. (CDC)

For millennia, at least since the time of the Egyptian pharaohs, smallpox had ravaged its way around the world. Caused by the variola virus, it was an exceptionally painful and gruesome disease. Victims suffered from fever and other flulike symptoms before developing a rash of the pustules that gave the disease its nickname: the speckled monster. It killed a third of its victims and left survivors disfigured, sometimes blind.

“Smallpox has been called one of the most loathsome diseases,” Dr. Henderson told The Washington Post in 1979. “I know that no matter how many visits I made to smallpox wards filled with seriously ill and dying patients, I always came away shaken.”

Populations had long sought to protect themselves from smallpox through crude methods of inoculation, the process by which a patient is intentionally exposed to a disease to provoke a mild reaction and thereby obtains immunity from a more serious infection.

In the 18th century, an English physician, Edward Jenner, discovered that exposure to the less dangerous cowpox virus produced immunity to smallpox. He is regarded as the father of the smallpox vaccine, which was perfected over the years and severely curtailed the spread of the disease in areas where the vaccine was distributed. Because of large-scale immunizations, the United States was free of smallpox by 1949.

But the disease continued to bedevil countries around the world, particularly in South America, South Asia and Africa. In the late 1950s, the Soviet Union began to apply pressure on the WHO, which is an agency of the United Nations, to mount a campaign to wipe out smallpox.

Many WHO officials were hesitant to embark on such an ambitious operation, fearing that a defeat would erode the organization’s credibility. Previous efforts to eliminate other diseases, such as yellow fever and malaria, had “failed spectacularly,” according to Jason Schwartz, a historian of medicine at the Yale School of Public Health.

When it was agreed that the WHO would take on the smallpox initiative, the organization turned to the United States, which, under Dr. Henderson’s leadership, had already launched a smallpox-eradication program in Africa. In an oral history with the online Global Health Chronicles, Dr. Henderson recalled that the WHO director general, the Brazilian malariologist Marcelino Candau, called the U.S. surgeon general with a demand.

“I want an American to run the program,” Candau said, “because when it goes down, when it fails, I want it to be seen that there is an American there and the U.S. is really responsible for this dreadful thing that you have launched the World Health Organization into, and the person I want is Henderson.”

Pressed by the surgeon general, and apprehensive about his chances of success, Dr. Henderson arrived in Geneva in 1966. For the next 11 years, he shuttled between Geneva and far-flung smallpox hot spots — obtaining funding, coordinating with nations including the Soviet Union amid Cold War tensions, and inspiring heroics from the tens of thousands of field workers who ventured into countries racked by deprivation, natural disaster, political instability and war.

The campaign, which cost an estimated total of $300 million, employed a strategy called ring vaccination that was credited to the American epidemiologist William Foege. Rather than attempting to vaccinate everyone — a technique determined to be superfluous — the WHO located smallpox patients, isolated them, vaccinated everyone who had contact with the victims, and then vaccinated everyone who had contact with those people.

The smallpox campaign benefited from an effective vaccine, ingeniously reconstituted in a freeze-dried form that could withstand the high temperatures of tropical environments. It was administered by a sharp, two-pronged rod that was easy for nonprofessionals to use. The nature of smallpox also offered advantages: With its telltale sores, it was easy to identify in patients, and it had no animal vector, or means of transmission.

Much credit for its success went to Dr. Henderson personally.

“He gives a sense of certainty on things,” Foege said in an interview, “and people like to follow a leader that is quite certain about what they are doing.”

When Dr. Henderson feared that the Soviet Union was delivering substandard vaccines for the effort, he traveled to Moscow, over the prohibition of his bosses, to confront authorities there, the New York Times reported. When the health minister under Ethiopian Emperor Haile Selassie proved insufficiently helpful, Dr. Henderson entered the country and cozied up to the emperor’s personal physician.

Dr. Henderson shared credit for his accomplishments with the many WHO collaborators who performed vaccinations in the field.

“The obstacles were unbelievable,” Dr. Henderson told the Times in 2011, recalling the efforts of Ciro de Quadros, a Brazilian epidemiologist who later helped lead an assault on polio. “The emperor assassinated, two revolutionary groups fighting, nine of his own teams kidnapped, even a helicopter captured and held for ransom. He kept the teams in the field — and that helicopter pilot went out and vaccinated all the rebels.”

Recalling their work together, Foege said that Dr. Henderson displayed profound concern for the field workers who risked their safety to carry out their work.

“I don’t know how many stories I’ve heard of the mothers of people who had gone to India calling him directly,” Foege said. “For some of them, it was their first time overseas. You can see why their parents might have been nervous if they didn’t hear from their child after a couple of weeks. Some of these mothers would call D.A. Henderson in Geneva and ask him to find out if their child was okay. And he would.”

To ensure total eradication, field workers offered rewards for reports of smallpox cases. When offers of cash went unanswered, Dr. Henderson told The Post, “we knew we had done it, but we couldn’t believe it.”

Ali Maow Maalin, a Somali who died in 2013, contracted the disease in 1977 and was identified as the world’s last patient with naturally occurring smallpox. Three years later, the World Health Assembly certified that smallpox had been eradicated.

Donald Ainslie Henderson was born in Lakewood, Ohio, outside of Cleveland, on Sept. 7, 1928. His mother was a nurse, and his father was an engineer.

He had not yet turned 20 when, in 1947, New York City suffered a smallpox outbreak. The episode, which resulted in the vaccination of millions, spurred Dr. Henderson’s interest in the disease and how it might be stopped.

He received a bachelor’s degree in chemistry from Ohio’s Oberlin College in 1950 and a medical degree in 1954 from the University of Rochester in New York. The next year, he joined the CDC, then called the Communicable Disease Center, where he was mentored by Alexander Langmuir, the founder of the CDC’s Epidemic Intelligence Service, a sort of epidemiological special forces.

“I decided I was never going to be a practicing doc,” Dr. Henderson once told an interviewer, according to the reference guide Current Biography. “It was just too dull, really.”

He received a master of public health degree from Johns Hopkins University in 1960. At the CDC, he became chief of the virus surveillance section before leading the African and then global smallpox eradication campaigns.

Dr. Henderson was the author of “Smallpox: The Death of a Disease” (2009). His honors included the National Medal of Science in 1986 and the Presidential Medal of Freedom, the nation’s highest civilian honor, in 2002.

Survivors include his wife of 64 years, the former Nana Bragg of Towson; three children, Leigh Henderson of Baltimore, David Henderson of Brooklyn and Douglas Henderson of Berlin.

When Dr. Henderson left the WHO in 1977, he quipped that as the chief expert on a disease that had been wiped out, he was “left there high and dry with no marketable skills,” with no option but to become a dean.

He joined Johns Hopkins, where he remained until 1990, later returning to found a center for civilian biodefense studies. Dr. Henderson served in the administrations of George H.W. Bush and Bill Clinton. After the Sept. 11, 2001, terrorist attacks and subsequent anthrax mailings, he served under President George W. Bush as director of the Office of Public Health Preparedness, a new unit to combat bioterrorism.

At the time, some U.S. intelligence analysts feared that Iraq or North Korea might possess strains of the smallpox virus and be capable of using them as biological weapons. Fears subsided after the 2003 invasion of Iraq, where no smallpox was found, but some experts still perceive a threat from North Korea.

The only officially sanctioned stores of the smallpox virus are held at heavily secured facilities at the CDC in Atlanta and at a Russian facility in Siberia. Some researchers contend that the samples should be preserved for use in the development of future vaccines or treatments.

Dr. Henderson strenuously argued that the samples should be destroyed because, in his view, any amount of smallpox was too dangerous to tolerate. A side effect of the eradication program — and one of the “horrendous ironies of history,” said “Hot Zone” author Preston — is that since no one in generations has been exposed to the virus, most of the world’s population would be vulnerable to it in the event of an outbreak.

“I feel very — what should we say? — dispirited,” Dr. Henderson told the Times in 2002. “Here we are, regressing to defend against something we thought was permanently defeated. We shouldn’t have to be doing this.”